Colony stimulating factors are proteins capable of influencing the growth and differentiation of cells responsible for the cellular components of blood in the body. Colony Stimulating factors have traditionally been defined by their ability to stimulate growth of colonies of bone marrow cells in semi-solid media. Macrophage colony stimulating factors are a subclass of colony stimulating factors that play a role in the regulation of immune responses by potentiating the proliferation and differentiation of macrophages from immature hematopoietic progenitor cells, and inducing effector functions of mature macrophages including secretion of interferon-.gamma, tumor necrosis factor and non-M-CSF colony stimulating activities.
The ability of certain factors produced in very low concentration in a variety of tissues to stimulate the growth and development of bone marrow progenitor cells into granulocytes and/or macrophages has been known for many years. The presence of such factors in sera, urine samples, and tissue extracts from a number of species is demonstrable using assays which measure the stimulation of colony formation by bone marrow cells plated in semi-solid culture medium. There is no known in vivo assay. As these factors induce the formation of such colonies, the factors collectively have been called Colony Stimulating Factors (CSF).
Colony Stimulating Factors have been purified from a number of tissue sources and species. Japanese Pat. No. 8,020,599 teaches of a rat myoid cell derived colony-stimulating factor capable of stimulating rat thymic macrophages and migroglia cells. Some colony stimulating factors are species restricted in their activity, such that CSF's derived from one species may lack colony forming activity in distantly related species (Shanafelt et al J Biol Chem 1991 Jul. 25; 266(21): 13804-10).
It has been shown that there are at least three subclasses of human CSF proteins defined according to the types of cells found in the resultant colonies. One subclass, CSF-1 results in colonies containing predominantly macrophages. Other subclasses produce colonies of both neutrophilic granulocytes and macrophages; which contain exclusively neutrophilic granulocytes; and which contain neutrophilic and eosinophilic granulocytes and macrophages.
Treatment of patients suffering from AIDS with colony stimulating factors, alone or together with erythropoietin and/or an antiviral agent and/or IL-2, is reported in PCT W087/03204 and U.S. Pat. No. 4,482,485. These references teach that CSF can be used for a supporting role in the treatment of cancer. In addition, EP 118,915 reports production of CSF for preventing and treating granulocytopenia and macrophagocytopenia in patients receiving cancer therapy, for preventing infections, and for treating patients with implanted bone marrow. In addition, CSFs stimulate nonspecific tumoricidal activity (Ralph et al, Immunobiol 172:194-204, 1986). CSF has no immediate direct role in activation of macrophages for tumoricidal and microbiocidal activities against fibrosarcoma 1023, lymphoma 18-8, and L. tropica amastigotes (Ralph et al., 76:10-21, 1983). The combination of CSF-1 and lymphokine has an added tumoricidal effect on murine sarcoma TU5 targets (Ralph et al., Cell. Immunol. 105:270-279, 1987). Warren et al. (J Immunol. 137:2281-2285, 1986) disclose that CSFs stimulate monocyte production of interferon, TNF and colony stimulating activity. Lee et al. (J. Immunol. 138:3019-3022, 1987) disclose CSF-induced resistance to viral infection in murine macrophages.